Sulphonamide derivatives

ABSTRACT

The invention concerns sulphonamide derivatives of the formula I ##STR1## wherein R 1  includes (1-4C)alkyl; 
     R 2  and R 3  together form --A 2  --X 2  --A 3  -- which defines a ring having 5 to 7 ring atoms, wherein A 2  and A 3  each is (1-3 C)alkylene and X 2  is oxy, thio, sulphinyl or sulphonyl; 
     A 1  is a direct link to X 1  or is (1-3 C)alkylene; 
     X 1  is oxy, thio, sulphinyl, sulphonyl or imino; 
     Ar is optionally substituted phenylene or Ar is pyridylene; 
     Q is nitrogen or of the formula CR 7 , wherein R 7  includes hydrogen, halogeno, (1-4 C)alkyl and (1-4 C)alkoxy; 
     each of R 4  and R 5  is (1-4 C)alkyl, (3-4 C)alkenyl, (3-4 C)alkynyl or optionally substituted phenyl, benzyl or pyridyl, or R 5  may be hydrogen; and 
     R 6  has any of the meanings defined for R 7  ; 
     or a pharmaceutically-acceptable salt thereof; processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

This invention concerns novel sulphonaimde deriatives and moreparticularly novel sulphonamide derivatives which are inhibitors of theenzyme 5-lipoxygenase (hereinafter referred to as 5-LO. The inventionalso concerns processes for the manufacture of said sulphonamidederivatives and novel pharmaceutical compositions containing them. Alsoincluded in the invention is the use of said sulphonamide derivatives inthe treatment of various inflammatory and/or allergic diseases in whichthe direct or indirect products of 5-LO catalysed oxidation ofarachidonic acid are involved, and the production of new medicaments forsuch use.

As stated above the sulphonamide derivatives described hereinafter areinhibitors of 5-LO, which enzyme is known to be involved in catalysingthe oxidation of arachidonic acid to give rise via a cascade process tothe physiologically active leukotrienes such as leukotriene B₄ (LTB₄)and the peptido-lipid leukotrienes such as leukotriene C₄ (LTC₄) andleukotriene D₄ (LTD₄) and various metabolites.

The biosynthetic relationship and physiological properties of theleukotrines are summarised by G. W. Taylor and S. R. Clarke in Trends inPharmacological Sciences, 1986, 7, 100-103. The leukotrienes and theirmetabolities have been implicated in the production and development ofvarious inflammatory and allergic diseases such as inflammation of thejoints (especially rheumatoid arthritis, osteoarthritis and gout),inflammation of the gastrointestinal tract (especially inflammatorybowel disease, ulcerative colitis and gastritis), skin disease(especially psoriasis, eczema and dermatitis) and respiratory disease(especially asthma, bronchitis and allergic rhinitis), and in theproduction and development of various cardiovascular and cerebrovasculardisorders such as myocardial infarction, angina and peripheral vasculardisease. In addition the leukotrienes are mediators of inflammatorydiseases by virtue of their ability to modulate lymphocyte and leukocytefunction. Other physiologically active metabolities of archidonic acid,such as the prostaglandins and thromboxanes, arise via the action of theenzyme cyclooxygenase on arachidonic acid.

It is disclosed in European Patent Application No. 0375404 A2 thatcertain heterocyclic derivatives possess inhibitory properties again5-LO. Copending European Patent Application No. 90306765.0 published onJan. 23, 1991 as European Patent Application No. 0409413) is concernedwith diaryl ether heterocycles which also possess inhibitory propertiesagainst 5-LO. We have now discovered that certain sulphonamidederivatives which possess some structural features which are similar tothose of the compounds disclosed in the above-mentioned applications butwhich possess other structural features, in particular a sulphonamidosubstituent, which were not envisaged in those earlier applications, areeffective inhibitors of the enzyme 5-LO and thus of leukotrienebiosyntheses. Thus such compounds are of value as therapeutic agents inthe treatment of, for example allergic conditions, psoriasis, asthma,cardiovasular and cerebrovascular disorders, and/or inflammatory andarthritic conditions, mediated alone or in part by one or moreleukotrienes.

According to the invention there is provided a sulphonamide derivativeof the formula I (set out hereinafter)

wherein R¹ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and whereinR² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 to 7 ring atoms, wherein A² and A³, which may be the sameor different, each is (1-3C)alkylene and X² is oxy, thio, sulphinyl orsulphonyl, and which ring may bear one, two or three substituents, whichmay be the same or different, selected from hydroxy, (1-4C)alkyl and(1-4C)alkoxy;

or wherein R¹ and R² together form a group of the formula --A² --X² --A³-- which together with the oxygen atom to which A² is attached and withthe carbon atom to which A³ is attached, defines a ring having 5 to 7ring atoms, wherein A² and A³, which may be the same or different, eachis (1-3C)alkylene and X² is oxy, thio, sulphinyl or sulphonyl and whichring may bear one, two or three (1-4C)alkyl substituents, and wherein R³is (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl;

wherein A¹ is a direct link to X¹ or is (1-3C)alkylene;

wherein X¹ is oxy, thio, sulphinyl, sulphonyl or imino;

wherein Ar is phenylene which may optionally bear one or twosubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carbamoyl, ureido, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl and (2-4C)alkanoylamino; or Aris pyridylene;

and wherein Q is nitrogen or of the formula CR⁷ wherein R⁷ is hydrogen,halogeno, (1-4C)alkyl, (1-4)alkoxy, hydroxy, amino, nitro, cyano,carbamoyl, ureido (1-4C)alkylamino, di-[(1-4C)alkyl]amino,fluoro-(1-4C)alkyl, (2-4C)alkanoylamino or (2-4C)alkenyl;

wherein R⁴ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl or R⁴ isphenyl, benzyl or pyridyl each of which may optionally bear one or twosubstituents selected from halogeno, (1-4C)alkoxy, (1-4C)alkyl, hydroxy,cyano, nitro, amino, trifluoromethyl, carbamoyl, ureido,(1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino;

wherein R⁵ is hydrogen, (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl, orR⁵ is phenyl, benzyl, or pyridyl each of which may optionally bear oneor two substituents selected from halogeno, (1-4C)alkoxy, (1-4C(alkyl,hydroxy, cyano, nitro, amino, trifluoromethyl, carbamoyl, ureido,(1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4c)alkanoylamino;

wherein R⁶ is hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy, hydroxy,amino, nitro, cyano, carbamoyl, ureido, (1-4C)alkylamino,di-[(1-4C)-alkyl]amino, fluoro-(1-4C)alkyl or (2-4C)alkanoylamino;

or R⁵ and R⁶ may be joined to form (2-4C)alkylene or (2-4C)alkenyleneeither of which may optionally bear one or two substitutents selectedfrom (1-4C)alkyl and halogeno;

or a pharmaceutically-acceptable salt thereof.

According to a further aspect of the invention there is provided asulphonamide derivative of the formula I as defined hereinbefore whereinR⁴ may be phenyl, benzyl, naphthyl, pyridyl or quinolyl each of whichmay optionally bear one or two substituents selected from halogeno,(1-4C)alkoxy, (1-4C)alkyl, hydroxy, cyano, nitro, amino,trifluoromethyl, carbamoyl, ureido, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino and (1-4C)alkoxycarbonyl; ora pharmaceutically-acceptable salt thereof.

The chemical formulae referred to herein by Roman numerals are set outfor convenience on a separate sheet hereinafter.

In this specification the generic term "alkyl" includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as "propyl" are specific for thestraight-chain version only and references to individual branched-chainalkyl groups as "isopropyl" are specific for the branched-chain versiononly. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds of theformula I defined above may exhibit the phenomenon of tautomerism andany formula drawing presented herein may represent only one of thepossible tautomeric forms, the invention includes in its definition anytautomeric form of a compound of the formula I which possesses theproperty of inhibiting 5-LO and is not to be limited merely to any onetautomeric form utilised within the formulae drawings.

It is further to be understood that, insofar as certain of the compoundsof formula I defined above may exist in optically active or racemicforms by virtue of one or more substituents containing an asymmetriccarbon atom, the invention includes in its definition any such opticallyactive or racemic form which posesses the property of inhibiting 5-LO.The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against 5-LO may beevaluated using the standard laboratory techniques referred tohereinafter.

Suitable values for the generic terms referred to above include thoseset out below.

A suitable value for R¹ when it is (1-4C)alkyl is, for example, methyl,ethyl, propyl or butyl; when it is (3-4C)alkenyl is, for example, allyl,2-butenyl; and when it is (3-4C)alkynyl is, for example, 2-propynyl or2-butynyl.

When R² and R³ together form a group of the formula --A² --X² --A³ --which, together with the carbon atom to which A² and A³ are attached,defines a ring having 5 to 7 ring atoms then a suitable value for A² andA₃, which may be the same or different, when each is (1-3 C)alkylene is,for example, methylene, ethylene or trimethylene. Suitable values forthe substituents which may be present on said 5- to 7-membered ringinclude for example:

    ______________________________________                                        for (1-4C)alkyl:                                                                            methyl, ethyl, propyl, isopropyl,                                             butyl and isobutyl;                                             for (1-4C)alkoxy:                                                                           methoxy, ethoxy, propoxy, isopropoxy                                          and butoxy.                                                     ______________________________________                                    

When R¹ and R² together form a group of the formula --A² --X² --A³ --which together with the oxygen atom to which A² is attached and with thecarbon atom to which A³ is attached, defines a ring having 5 to 7 ringatoms then a suitable value for A² and A³, which may be the same ordifferent, when each is (1-3C)alkylene is, for example, methylene,ethylene or trimethylene. Suitable values for the (1-4C)alkylsubstituents which may be present on said 5- to 7-membered ring include,for example, methyl, ethyl, propyl, isopropyl and butyl.

A suitable value for R³ when it is (1-4C)alkyl is, for example, methyl,ethyl, propyl or butyl; when it is (2-4c)alkenyl is, for example, vinyl,allyl, 2-butenyl or 3-butenyl; and when it is (2-4C)alkynyl is, forexample, ethynyl, 2-propynyl or 2-butynyl.

A suitable value for A¹ when it is (1-3C)alkylene is, for example,methylene, ethylene or trimethylene.

A suitable value for Ar when it is phenylene is, for example,1,3-phenylene or 1,4-phenylene.

A suitable value for Ar when it is pyridylene is, for example 3,5- or2,6-pyridylene.

A suitable value for a halogeno substituent which may be present on Aris, for example, fluoro, chloro, bromo or iodo.

A suitable value for a (2-4C)alkanoylamino substituent which may bepresent on Ar is, for example, acetamido, propionamido or butyramido.

A suitable value for a (1-4C)alkyl substituent which may be present onAr is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl or tert-butyl.

A suitable value for a (1-4C)alkoxy substituent which may be present onAr is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

A suitable value for a (1-14C)alkylamino substitutent which may bepresent on Ar is, for example, methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, sec-butylamino ortert-butylamino.

A suitable value for a di-[(1-4C)alkyl]amino substituent whic ay bepresent on Ar is, for example, dimethylamino, diethylamino,dipropylamino, dibutylamino or ethylmethylamino.

A suitable value for a fluoro-(1-4C)alkyl substitutent which may bepresent on Ar is, for example, fluoromethyl, fluoroethyl, fluoropropyl,fluorisoproyl, fluorobutyl, difluoromethyl or trifluoroethyl.

Suitable values for R⁷ include, for example:

    ______________________________________                                        for halogeno:  fluoro, chloro, bromo and iodo;                                for (1-4C)alkyl:                                                                             methyl, ethyl, propyl, isopropyl,                                             butyl, isobutyl, sec-butyl and                                                tert-butyl;                                                    for (1-4C)alkoxy:                                                                            methoxy, ethoxy, propoxy, isopropoxy                                          and butoxy;                                                    for (1-4C)alkylamino:                                                                        methylamino, ethylamino, propyl-                                              amino, isopropylamino, butylamino,                                            sec-butylamino and tert-butylamino;                            for di-[(1-4C)alkyl]amino:                                                                   dimethylamino, diethylamino,                                                  dipropylamino, ethylmethylamino and                                           dibutylamino;                                                  for fluoro-(1-4C)alkyl:                                                                      fluoromethyl, fluoroethyl,                                                    difluoromethyl, trifluoromethyl,                                              fluoropropyl, fluorobutyl and                                                 fluoroisopropyl;                                               for (2-4C)alkanoylamino:                                                                     acetamido, propionamido and                                                   butyramido;                                                    for (2-4C)alkenyl:                                                                           vinyl, allyl, 2-butenyl and 3-butenyl.                         ______________________________________                                    

A suitable value for R⁴ when is it (1-4C)alkyl is, for example, methyl,ethyl, propyl, ispropyl, butyl, sec-butyl or tert-butyl.

A suitable value for R⁴ when it is (3-4C)alkenyl is, for example, allyl,2-butenyl or 3-butenyl.

A suitable value for R⁴ when it is (3-4C)alkynyl is, for example,2-propynyl or 2-butynyl.

A suitable value for R⁴ or R⁵ when it is pyridyl is, for example,2-pyridyl, 3-pyridyl or 4-pyridyl.

A suitable value for R⁴ when it is naphthyl is, for example, 1-naphthylor 2-naphthyl, especially 1-naphtyl.

A suitable value for R⁴ when it is quinolyl is, for example, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, especially 8-quinolyl.

A suitable value for R⁵ when it is (1-4C)alkyl is, for example, methyl,ethyl, propyl, ispropyl, butyl, sec-butyl or tert-butyl.

A suitable value for R⁵ when it is (3-4C)alkenyl is, for example, allyl,2-butenyl or 3-butenyl.

A suitable value for R⁵ when it is (3-4C)alkynyl is, for example,2-propynyl or 2-butynyl.

Suitable values for substituents which may be present on R⁴ or R⁵ wheneach is phenyl, benzyl, naphthyl, pyridyl or quinolyl include, forexample:

    ______________________________________                                        for halogeno:  fluoro, chloro, bromo and iodo;                                for (1-4C)alkoxy:                                                                            methoxy, ethoxy, propoxy, isopropoxy                                          and butoxy;                                                    for (1-4C)alkyl:                                                                             methyl, ethyl, propyl, isopropyl,                                             sec-butyl and tert-butyl;                                      for (1-4C)alkylamino:                                                                        methylamino, ethylamino, propyl-                                              amino, isopropylamino, butylamino,                                            sec-butylamino and tert-butylamino;                            for di-[(1-4C)alkyl]amino:                                                                   dimethylamino, diethylamino,                                                  dipropylamino, dibutylamino and                                               ethylmethylamino;                                              for (2-4C)alkanoylamino:                                                                     acetamido, propionamido and                                                   butyramido;                                                    for (1-4C)alkoxycarbonyl:                                                                    methoxycarbonyl, ethoxycarbonyl,                                              propoxycarbonyl and tert-                                                     butoxycarbonyl.                                                ______________________________________                                    

Suitable values for R⁶ include, for example:

    ______________________________________                                        for halogeno:  fluoro, chloro, bromo and iodo;                                for (1-4C)alkyl:                                                                             methyl, ethyl, propyl, isopropyl,                                             butyl, isobutyl, sec-butyl and                                                tert-butyl;                                                    for (1-4C)alkoxy:                                                                            methoxy, ethoxy, propoxy, isopropoxy                                          and butoxy;                                                    for (1-4C)alkylamino:                                                                        methylamino, ethylamino, propyl-                                              amino, isopropylamino, butylamino,                                            sec-butylamino and tert-butylamino;                            for di[(1-4C)alkyl]amino:                                                                    dimethylamino, diethylamino,                                                  dipropylamino, ethylmethylamino and                                           dibutylamino;                                                  for fluoro-(1-4C)alkyl:                                                                      fluoromethyl, fluoroethyl,                                                    difluoromethyl, trifluoromethyl,                                              fluoropropyl, fluorobutyl and                                                 fluoroisopropyl;                                               for (2-4C)alkanoylamino:                                                                     acetamido, propionamido and                                                   butyramido;                                                    ______________________________________                                    

A suitable value for R⁵ and R⁶ when they are joined to form(2-4C)alkylene is, for example, ethylene or trimethylene. ConvenientlyR⁶ is located at the position ortho to the R⁴ SO₂ NR⁵ group.

A suitable value for R⁵ and R⁶ when they are joined to form(2-4C)alkylene is, for example, vinylene, prop-1-en-1,3diyl orprop-2-en-1,3-diyl. Conveniently R⁶ is located at the position ortho tothe R⁴ SO₂ NR⁵ group.

Suitable values for the substituents which may be present on the(2-4C)alkylene or (2-4C)alkenylene group when R⁵ and R⁶ are joinedinclude, for example:

    ______________________________________                                        for halogeno:  fluoro, chloro, bromo and iodo;                                for (1-4C)alkyl:                                                                             methyl, ethyl and propyl.                                      ______________________________________                                    

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a physiologically-acceptable cation, for example a salt withmethylamine, dimethylamine, triethylamine, piperidine, morpholine ortris(2-hydroxyethyl)amine.

Particular novel compounds of the invention include, for example,sulphonamide derivatives of the formula I wherein:

(a) R¹ is methyl, ethyl, allyl or 2-propynyl; and Q, R², R³, A¹, X¹, Ar,R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(b) R² and R³ together form a group of the formula --A² --X² --A³ --which, together with the carbon atom to which A² and A³ are attached,defines a ring having 5 to 7 ring atoms, wherein A² and A³, which may bethe same or different, each is methylene, ethylene or trimethylene andX² is oxy, and which ring may bear one or two substituents selected fromhydroxy, methyl, ethyl, propyl, methoxy and ethoxy; and Q, R¹, A¹, X¹,Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore:

(c) R¹ and R² together form a group of the formula --A² --X² --A³ --which, together with the oxygen atom to which A² is attached and withthe carbon atom to which A³ is attached, defines a ring having 5 to 7ring atoms, wherein A² and A³, which may be the same or different, eachis methylene or ethylene and X² is oxy, and which ring may bear one, twoor three substituents selected from methyl, ethyl and propyl, and R³ ismethyl or ethyl; and Q, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any of themeanings defined hereinbefore;

(d) A¹ is a direct link to X¹, and X¹ is oxy, thio, sulphinyl orsulphonyl; and Q, R¹, R², R³, Ar, R⁴, R⁵ and R⁶ have any of the meaningsdefined hereinbefore;

(e) A¹ is methylene and X¹ is oxy, thio, sulphinyl or sulphonyl; and Q,R¹, R², R³, Ar, R⁴, R⁵ and R⁶ have any of the meanings definedhereinbefore;

(f) Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear oneor two substituents selected from fluoro, chloro, hydroxy, amino, nitro,ureido, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl andacetamido; and Q, A¹, X¹, R¹, R², R³, R⁴, R⁵ and R⁶ have any of themeanings defined hereinbefore;

(g) Ar is 3,5-pyridylene; and Q, A¹, X¹, R¹, R², R³, R⁴, R⁵ and R⁶ haveany of the meanings defined hereinbefore;

(h) Q is nitrogen or a group of the formula CR⁷, wherein R⁷ is hydrogen,methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoro, chloro orhydroxy; and R¹, R², R³, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any of themeanings defined hereinbefore;

(i) R⁴ is methyl, ethyl, propyl, phenyl, benzyl or 3-pyridyl each ofwhich may bear one or two substituents selected from fluoro, chloro,methoxy, ethoxy, methyl, ethyl or hydroxy; and Q, R¹, R², R³, A¹, X¹,Ar, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(j) R⁴ is methyl, ethyl, propyl, phenyl, benzyl, 1-naphthyl, 3-pyridylor 8-quinolyl each of which may bear one or two substituents selectedfrom fluoro, chloro, methoxy, ethoxy, methyl, hydroxy, methoxycarbonylor ethoxycarbonyl; and Q, R¹, R², R³, A¹, X¹, Ar, R⁵ and R⁶ have any ofthe meanings defined hereinbefore;

(k) R⁵ is hydrogen, methyl, ethyl, propyl, allyl, phenyl or benzyl eachof which may bear one or two substituents selected from fluoro, chloro,methoxy, ethoxy, methyl, ethyl or hydroxy; and Q, R¹, R², R³, A¹, X¹,Ar, R⁴ and R⁶ have any of the meanings defined hereinbefore;

(l) R⁶ is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, fluoro,chloro or hydroxy; and Q, R¹, R², R³, A¹, X¹, Ar, R⁴ and R⁵ have any ofthe meanings defined hereinbefore;

(m) R⁵ and R⁶ are joined together to form ethylene, trimethylene orvinylene which may bear one or two substituents selected from methyl,ethyl and propyl; and Q, R¹, R², R³, A¹, X¹, Ar and R⁴ have any of themeanings defined hereinbefore;

(n) Q is nitrogen; and R¹, R², R³, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any ofthe meanings defined hereinbefore;

(o) Q is a group of the formula CR⁷, wherein R⁷ is hydrogen, fluoro,chloro, methyl, ethyl or methoxy; and R¹, R², R³, A¹, X¹, Ar, R⁴, R⁵ andR⁶ have any of the meanings defined hereinbefore;

(p) R⁴ is methyl, ethyl or propyl or R⁴ is phenyl which may bear one ortwo substituents selected from fluoro, chloro, methyl or methoxy; and Q,R¹, R², R³, A¹, X¹ Ar, R⁵ and R⁶ have any of the meanings definedhereinbefore;

(q) R⁵ is hydrogen, methyl, ethyl, propyl or allyl or R⁵ is phenyl orbenzyl which may bear one or two substituents selected from fluoro,chloro, methyl or methoxy; and Q, R¹, R², R³, A¹, X¹, Ar, R⁴ and R⁶ haveany of the meanings defined hereinbefore;

(r) R⁵ is hydrogen; and Q, R¹, R², R³, A¹, X¹, Ar, R⁴ and R⁶ have any ofthe meanings defined hereinbefore; or

(s) R⁶ is located at the position ortho to the R⁴ SO₂ NR⁵ group and R⁵and R⁶ are joined together to form ethylene or trimethylene; and Q, R¹,R², R³, A¹, X¹, Ar and R⁴ have any of the meanings defined hereinbefore;

or a pharmaceutically-acceptable salt thereof.

A preferred compound of the invention comprises a sulphonamidederivative of the formula I wherein

R¹ is methyl, ethyl, allyl or 2-propynyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methyleneor ethylene, and X² is oxy, and which ring may bear one or twosubstituents selected from methyl, ethyl, propyl, methoxy and ethoxy;

or R¹ and R² together form a group of the formula --A² --X² --A³ --which, together with the oxygen atom to which A² is attached and withthe carbon atom to which A³ is attached, defines a ring having 5 or 6ring atoms, wherein A² is methylene, A³ is methylene or ethylene, and X²is oxy, and which ring may bear one, two or three substituents selectedfrom methyl, ethyl and propyl, and R³ is methyl or ethyl;

A¹ is a direct link to X¹ or is methylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one ortwo substituents selected from fluoro, chloro, hydroxy, amino, nitro,ureido, methoxy, dimethylamino, trifluoromethyl and acetamido; or Ar is3,5-pyridylene;

Q is nitrogen or of the formula CR⁷ wherein R⁷ is hydrogen, fluoro,chloro, methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, amino,methylamino, dimethylamino or trifluoromethyl;

R⁴ is methyl, ethyl, propyl, allyl, phenyl, benzyl, 3-pyridyl,2-hydroxyethyl, 3-hydroxypropyl, 2-chloroethyl or 3-chloropropyl;

R⁵ is hydrogen, methyl, ethyl, propyl, phenyl, benzyl, allyl, 3-pyridyl,2-hydroxyethyl, 3-hydroxypropyl, 2-chloroethyl, 3-chloropropyl or2-methoxyethyl; and

R⁶ is hydrogen, fluoro, chloro, methyl, ethyl, propyl, methoxy, ethoxy,hydroxy, amino, methylamino, dimethylamino or trifluoromethyl; or

R⁵ and R⁶ may be joined to form ethylene, trimethylene or vinylene;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamidederivative of the formula I wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and X²is oxy, and which ring may bear a methyl or ethyl substituent alpha toX² ;

A¹ is a direct link to X¹, or is methylene;

X¹ is thio or oxy;

Ar is 1,3-phenylene which may optionally bear a fluoro substituent;

Q is nitrogen or of the formula CR⁷ wherein R⁷ is hydrogen, methyl orchloro;

R⁴ is methyl, ethyl or phenyl;

R⁵ is hydrogen, methyl, ethyl, allyl or benzyl; and

R⁶ is hydrogen, methyl or chloro; or

R⁵ and R⁶ may be joined to form ethylene or trimethylene;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamidederivative of the formula I wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and X²is oxy, and which ring may bear a methyl or ethyl substituent alpha toX² ;

A¹ is a direct link to X¹, or is methylene;

X¹ is thio or oxy;

Ar is 1,3-phenylene which may optionally bear a fluoro substituent;

Q is of the formula CR⁷ wherein R⁷ is hydrogen, methyl or chloro;

R⁴ is methyl, ethyl or phenyl;

R⁵ is hydrogen;

R⁶ is hydrogen, methyl, fluoro or chloro;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamidederivative of the formula I, wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and X²is oxy, and which ring may bear a methyl substituent alpha to X² ;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar is 1,3-phenylene;

Q is of the formula CR⁷ wherein R⁷ is hydrogen;

R⁴ is methyl;

R⁵ is methyl or ethyl; and

R⁶ is hydrogen or chloro;

of a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamidederivative of the formula I wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and X²is oxy, and which ring may bear a methyl or ethyl substituent alpha toX² ;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar is 1,3-phenylene which may optionally bear a fluoro substituent;

Q is of the formula CR⁷ wherein R⁷ is hydrogen or chloro;

R⁴ is methyl, ethyl, phenyl, 2-methoxycarbonylphenyl or 8-quinolyl;

R⁵ is hydrogen;

R⁶ is hydrogen, fluoro or chloro;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamidederivative of the formula I, wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which ,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and X²is oxy, and which ring may bear a methyl substituent alpha to X² ;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;

Q is of the formula CR⁷ wherein R⁷ is hydrogen or chloro;

R⁴ is methyl;

R⁵ is hydrogen; and

R⁶ is hydrogen, fluoro or chloro;

or a pharmaceutically-acceptable salt thereof.

A specific especially preferred compound of the invention is, forexample, the following sulphonamide derivative of the formula I, or apharmaceutically-acceptable salt thereof:

N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamide,

N-{3-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylethanesulphonamide,

N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-ethylmethanesulphonamideor

N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylethanesulphonamide.

A further specific especially preferred compound of the invention is,for example, the following sulphonamide derivative of the formula I, ora pharmaceutically-acceptable salt thereof:

N-{2-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}methanesulphonamide,

N-{2-chloro-4-[4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}methanesulphonamide,

N-{3-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}methansulphonamideor

N-{2-fluoro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}methanesulphonamide.

A compound of the invention comprising a sulphonamide derivative of theformula I, or a pharmaceutically-acceptable salt thereof, may beprepared by any process known to be applicable to the preparation ofstructurally-related compounds. Such procedures are provided as afurther feature of the invention and are illustrated by the followingrepresentative examples in which, unless otherwise stated R¹, R², R³,A¹, X¹, Ar, Q, R⁴, R⁵, R⁶ and R⁷ have any of the meanings definedhereinbefore.

(a) The coupling, conveniently in the presence of a suitable base, of acompound of the formula II with a compound of the formula III, wherein Zis a displaceable group; provided that, when there is an amino,alkylamino or hydroxy group in Ar, R², R³, R⁴, R⁵, R⁶ or R⁷, any amino,alkylamino or hydroxy group may be protected by a conventionalprotecting group or alternatively any such group need not be protected,whereafter any desired protecting group in Ar, R², R³, R⁴, R⁵, R⁶ and R⁷is removed by conventional means.

A suitable displaceable group Z is, for example, a halogeno orsulphonyloxy group, for example a chloro, bromo, iodo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

A suitable base for the coupling reaction is, for example, an alkali oralkaline earth metal carbonate, (1-4C)alkoxide, hydroxide or hydride,for example sodium carbonate, potassium carbonate, sodium ethoxide,potassium butoxide, sodium hydroxide, potassium hydroxide, sodiumhydride or potassium hydride. The coupling reaction is convenientlyperformed in a suitable inert solvent or diluent, for exampleN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, andat a temperature in the range, for example 10° to 190° C., convenientlyat or near 140° C.

Conveniently the reaction may be performed in the presence of a suitablecatalyst, for example a metallic catalyst, for example palladium(O) orcopper(I) such as tetrakis(triphenylphosphine)palladium, cuprouschloride or cuprous bromide.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group for example a (2-4C)alkanoyl group (especiallyacetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl,ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group(especially benzyloxycarbonyl) or an aroyl group (especially benzoyl).The deprotection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or alkoxycarbonyl or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid andan arylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-charcoal.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example a (2-4C)alkanoyl group (especially acetyl), an aroylgroup (especially benzoyl) or an arylmethyl group (especially benzyl).The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example byhydrogenation over a catalyst such as palladium-on-charcoal.

The starting materials of the formula II and of the formula III may beobtained by standard procedures of organic chemistry. The preparation ofsuch starting materials is described within the accompanyingnon-limiting Examples which are provided for the purpose of illustrationonly. Alternatively necessary starting materials of the formula III areobtainable by analogous procedures to those illustrated in accompanyingScheme I (set out hereinafter) or by modifications thereto which arewithin the ordinary skill of an organic chemist.

A suitable protecting group R⁸, as employed in Scheme I, is any one ofthe many such groups known in the art and inlcudes any appropriateprotecting group as defined hereinbefore. Examples of such groups aregiven in Scheme I. The conditions for the introduction and removal ofsuch protecting groups are described in standard textbooks or organicchemistry such as, for example, "Protective Groups in Organic Synthesis"by T W Green (J Wiley and Sons, 1981).

(b) The coupling, conveniently in the presence of a suitable base asdefined hereinbefore, of a compound of the formula IV with a compound ofthe formula V wherein Z is a displaceable group as defined hereinbefore;provided that, when there is an amino, alkylamino or hydroxy group inAr, R², R³, R⁴, R⁵, R⁶ or R⁷ any amino, alkylamino or hydroxy group maybe protected by a conventional protecting group as defined hereinbeforeor alternatively any such group need not be protected, whereafter anyundesired protecting group in Ar, R², R³, R⁴, R⁵, R⁶ or R⁷ is removed byconventional means.

The coupling reaction is conveniently performed in a suitable inertsolvent as defined hereinbefore and at a temperature in the range, forexample, 10° to 190° C., conveniently at or near 140° C. The reactionmay conveniently be performed in the presence of a suitable catalyst asdefined hereinbefore.

Conveniently intermediates of the formula V wherein Z, Ar, R¹, R² and R³have the meanings defined hereinbefore, may be obtained by way ofcompounds of the formula Z--Ar--Y, wherein Z and Ar have the meaningsdefined hereinbefore and Y is, for example, a halogeno, formyl,alkanoyl, nitrile or alkoxycarbonyl group, as illustrated inaccompanying Scheme II (set out hereinafter).

It will also be appreciated that the intermediate of the formula V mayconveniently be obtained from the compound of the formula Z--Ar--Y, asdefined hereinbefore, by reversing the order of introduction of thegroups R² and R³ which is used in Scheme II.

(c) The alkylation, conveniently in the presence of a suitable base asdefined hereinbefore, of a compound of the formula VI with a compound ofthe formula R¹ --Z, wherein R¹ and Z have the meanings definedhereinbefore; provided that, when there is an amino, alkylamino orhydroxy group in Ar, R², R³, R⁴, R⁵, R⁶ or R⁷ any amino, alkylamino orhydroxy group may be protected by a conventional protecting group oralternatively any such group need not be protected, whereafter anyundesired protecting group in Ar, R², R³, R⁴, R⁵, R⁶ and R⁷ is removedby conventional means.

The tertiary alcohol starting material of the formula VI may be obtainedby standard procedures of organic chemistry. Conveniently, and asillustrated in accompanying Scheme III (set out hereinafter),intermediates of the formula VIII wherein A¹, X¹, Ar, Q, R⁴, R⁵ and R⁶have the meanings defined hereinbefore and Y is, for example, a formyl,nitrile or alkoxycarbonyl group may be utilised in the preparation ofthe tertiary alcohol starting material of the formula VI.

(d) The sulphonamidification, conveniently in the presence of a Lewisbase such as an organic amine, for example triethylamine, pyridine,4-dimethylaminopyridine, morpholine and piperidine, of a compound of theformula VII with a compound of the formula R⁴ SO₂ Z, wherein Z is adisplaceable group such as halogeno for example chloro, bromo or iodo;provided that when there is an amino, alkylamino or hydroxy group in Ar,R², R³, R⁵, R⁶ or R⁷, any amino, alkylamino or hydroxy group isprotected by a conventional protecting group as defined hereinbefore,whereafter any undesired protecting group in Ar, R², R³, R⁵, R⁶ or R⁷ isremoved by conventional means.

The reaction is conveniently performed in a suitable organic solvent,for example dichloromethane, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane,N-methylpyrrolidin-2-one or tetrahydrofuran and at a temperature in therange of -40° C. to 80° C. conveniently in the range 0°-25° C.

the starting material of the formula VII may be obtained by standardprocedures of organic chemistry such as by analogous procedures to thosedescribed hereinbefore in process variants (a) to (c) above or bymodifications thereto which are within the skill of an organic chemist.

(e) For the production of those compounds of the formula I wherein X¹ isa sulphinyl or sulphonyl group, or wherein R² and R³ together form agroup of the formula --A² --X² --A³ -- and X² is a sulphinyl orsulphonyl group, the oxidation of a compound of the formula I wherein X¹is a thio group, or wherein R² and R³ together form a group of theformula --A² --X² --A³ -- and X² is a thio group.

A suitable oxidising agent is, for example, any agent known in the artfor the oxidation of thio to sulphinyl and/or sulphonyl, for example,hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic orperoxyacetic acid), an alkali metal peroxysulphate (such as potassiumperoxymonosulphate), chromium trioxide or gaseous oxygen in the presenceof platinum. The oxidation is generally carried out under as mildconditions as possible and with the required stoichiometric amount ofoxidising agent in order to reduce the risk of over oxidation and damageto other functional groups. In general the reaction is carried out in asuitable solvent or diluent such as methylene chloride, chloroform,acetone, tetrahydrofuran or tert-butyl methyl ether and at atemperature, for example, at or near ambient temperature, that is in therange 15° to 35° C. When a compound carrying a sulphinyl group isrequired a milder oxidising agent may also be used, for example sodiumor potassium metaperiodate, conveniently in a polar solvent such asacetic acid or ethanol. It will be appreciated that when a compound ofthe formula I containing a sulphonyl group is required, it may beobtained by oxidation of the corresponding sulphinyl compound as well asthe corresponding thio compound.

When a pharmaceutically-acceptable salt of a novel compound of theformula I is required, it may be obtained, for example, by reaction ofsaid compound with a suitable acid or base using a conventionalprocedure. When an optically active form of a compound of the formula Iis required, it may be obtained by carrying out one of the aforesaidprocedures using an optically active starting material, or by resolutionof a racemic form of said compound using a conventional procedure.

Many of the intermediates defined herein are novel, for example those ofthe formulae IV and VI and these are provided as a further feature ofthe invention.

As stated previously, the novel compounds of the formula I areinhibitors of the enzyme 5-LO. The effects of this inhibition may bedemonstrated using one or more of the standard procedures set out below:

a) An in vitro assay system involving incubating a test compound withheparinised human blood, prior to challenge with the calcium ionophoreA23187 and then indirectly measuring the inhibitory effects on 5-LO byassaying the amount of LTB₄ using specific radioimmunoassays describedby Carey and Forder (Prostaglandins, Leukotrienes Med., 1986, 22, 57;Prostaglandins, 1984, 28, 666; Brit. J. Pharmacol., 1985, 84, 34P) whichinvolve the use of a protein-LTB₄ conjugate produced using the procedureof Young et alia (Prostaglandins, 1983, 26(4), 605-613). The effects ofa test compound on the enzyme cyclooxygenase (which is involved in thealternative metabolic pathway for arachidonic acid and gives rise toprostaglandins, thromboxanes and related metabolites) may be measured atthe same time using the specific radioimmunoassay for thromboxane B₂(TxB₂) described by Carey and Forder (see above). This test provides anindication of the effects of a test compound against 5-LO and alsocyclooxygenase in the presence of blood cells and proteins. It permitsthe selectivity of the inhibitory effect on 5-LO or cyclooxygenase to beassessed.

b) An ex vivo assay system, which is a variation of test a) above,involving administration of a test compound (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to carboxymethylcellulose), bloodcollection, heparinisation, challenge with A23187 and radioimmunoassayof LTB₄ and TxB₂. This test provides an indication of thebioavailability of a test compound as an inhibitor of 5-LO orcyclooxygenase.

c) An in vivo system involving measuring the effects of a test compoundadministered orally against the liberation of LTB₄ induced by zymosanwithin an air pouch generated within the subcutaneous tissue of the backof male rats. The rats are anaesthetised and air pouches are formed bythe injection of sterile air (20 ml). A further injection of air (10 ml)is similarly given after 3 days. At 6 days after the initial airinjection the test compound is administered (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to hydroxypropylmethylcellulose), followedby the intrapouch injection of zymosan (1 ml of a 1% suspension inphysiological saline). After 3 hours the rats are killed, the airpouches are lavaged with physiological saline, and the specificradioimmunoassay described above is used to assay LTB₄ in the washings.This test provides an indication of inhibitory effects against 5-LO inan inflammatory milieu.

Although the pharmacological properties of the compounds of the formulaI vary with structural changes as expected, in general compounds of theformula I possess 5-LO inhibitory effects at the followingconcentrations or doses in one or more of the above tests a)-c):

    ______________________________________                                        Test a):                                                                             IC.sub.50 (LTB.sub.4) in the range, for example, 0.01-40 μM                IC.sub.50 (TxB.sub.2) in the range, for example, 40-200 μM;         Test b):                                                                             oral ED.sub.50 (LTB.sub.4) in the range, for example,                         1-100 mg/kg;                                                           Test c):                                                                             oral ED.sub.50 (LTB.sub.4) in the range, for example,                         0.5-50 mg/kg.                                                          ______________________________________                                    

No overt toxicity or other untoward effects are present in tests b)and/or c) when compound of the formula I are administered at severalmultiples of their minimum inhibitory dose or concentration.

Thus, by way of example, the compoundN-{3-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamidehas an IC₅₀ of 0.09 μM against LTB₄ in test a), and an oral ED₅₀ of 1mg/kg versus LTB ₄ in test c); and the compoundN-{2-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl)-methanesulphonamidehas an IC₅₀ of 1 μM against LTB ₄ in test a), and an oral ED₅₀ of 1.5mg/kg versus LTB₄ in test c). In general those compounds of the formulaI which are particularly preferred have an IC₅₀ of <1 μM against LTB₄ intest a), and an oral ED₅₀ of <100 mg/kg against LTB₄ in tests b) and/orc).

These compounds are examples of compounds of the invention which showselective inhibitory properties for 5-LO as opposed to cyclooxygenase,which selective properties are expected to impart improved therapeuticproperties, for example, a reduction in or freedom from thegastrointestinal side-effects frequently associated with cyclooxygenaseinhibitors such as indomethacin.

According to a further featues of the invention there is provided apharmaceutical composition which comprises a sulphonamide derivative ofthe formula I, or a pharmaceutically-acceptable salt thereof, inassociation with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops; for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powderor a liquid aerosol; for sub-lingual or buccal use, for example a tabletor capsule; or for parenteral use (including intravenous, subcutaneous,intramuscular, intravascular or infusion), for example a sterile aqueousor oily solution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

The amount of active ingredient (that is a sulphonamide derivative ofthe formula I, or a pharmaceutically-acceptable salt thereof) that iscombined with one ore more excipients to produce a single dosage formwill necessarily vary depending upon the host treated and the particularroute of administration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient.

According to a further feature of the invention there is provided asulphonamide derivative of the formula I, or apharmaceutically-acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy.

The invention also includes a method of treating a disease or medicalcondition mediated alone or in part by one or more leukotrienes whichcomprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as defined above.The invention also provides the use of such an active ingredient in theproduction of a new medicament for use in a leukotriene mediated diseaseor medical condition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the condition, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, compounds of the formula I are useful intreating those allergic and inflammatory conditions which are due aloneor in part to the effects of the metabolites of arachidonic acid arisingby the linear (5-LO catalysed) pathway and in particular theleukotrienes, the production of which is mediated by 5-LO. As previouslymentioned, such conditions include, for example, asthmatic conditions,allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopicdermatitis, cardiovascular and cerebrovascular disorders of aninflammatory nature, arthritic and inflammatory joint disease, andinflammatory bowel diseases.

In using a compound of the formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used.

Although the compounds of the formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the enzyme 5-LO.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

By virtue of their effects on leukotriene production, the compounds ofthe formula I have certain cytoprotective effects, for example they areuseful in reducing or suppressing certain of the adversegastrointestinal effects of the cyclooxygenase inhibitory non-steroidalanti-inflammatory agents (NSAIA), such as indomethacine, acetylsalicylicacid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore,co-administration of a 5-LO inhibitor of the formula I with a NSAIA canresult in a reduction in the quantity of the latter agent needed toproduce a therapeutic effect, thereby reducing the likelihood of adverseside-effects. According to a further feature of the invention there isprovided a pharmaceutical composition which comprises a sulphonamidederivative of the formula I, or a pharmaceutically-acceptable saltthereof as defined hereinbefore, in conjunction or admixture with acyclooxygenase inhibitory non-steroidal anti-inflammatory agent (such asthose mentioned above), and a pharmaceutically-acceptable diluent orcarrier.

The cytoprotective effects of the compounds of the formula I may bedemonstrated, for example in a standard laboratory model which assessesprotection against indomethacin-induced or ethanol-induced ulceration inthe gastrointestinal tract of rats.

The compositions of the invention may in addition contain one or moretherapeutic or prophylactic agents known to be of value for the diseaseunder treatment. Thus, for example a known platelet aggregationinhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergicblocker or a vasodilator may usefully also be present in apharmaceutical composition of the invention for use in treating a heartor vascular disease or condition. Similarly, by way of example, ananti-histamine, steroid (such as beclomethasone dipropionate), sodiumcromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulantmay usefully also be present in a pharmaceutical composition of theinvention for use in treating a pulmonary disease or condition.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at room temperature, that is in therange 18°-25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the structures of the end-products of the formula I were confirmedby NMR and mass spectral techniques; unless otherwise stated, CDCl₃solutions of the end-products of the formula I were used for thedetermination of the NMR spectral data, chemical shift values weremeasured on the delta scale;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

THF: tetrahydrofuran;

DMF: N,N-dimethylformamide.

EXAMPLE 1

A solution of N-(4-bromomethylphenyl)-N-methylmethanesulphonamide (0.36g), 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran (0.27 g) andpotassium carbonate (0.36 g) in DMF was stirred at ambient temperaturefor 18 hours. The mixture was then partitioned between ethyl acetate (75ml) and water (50 ml) and the organic phase washed with brine (50 ml)and dried (MgSO₄). The solvent was evaporated and the product purifiedby column chromatography. Thus was obtainedN-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenoxymethyl]phenyl}-N-methylmethanesulphonamide(0.23 g, 47%), m.p. 128°-132° C. (recrystallised from ethylacetate/hexane).

NMR Spectrum 1.82-2.05 (4H, m), 2.85 (3H, s), 2.98 (3H, s), 3.75-3.91(4H, m), 5.04 (2H, 2), 6.60 (1H, m), 6.73 (1H, m), 6.80 (1H, m),7.38-7.50 (4H, m).

The 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran used asstarting material was prepared as described in European PatentApplication No. 0385662 (example 2 therein).

The N-(4-bromomethylphenyl)-N-methylmethansulphonamide used as startingmaterial was obtained as follows:

A solution of p-methyl-N-methylaniline (5.00 g) and triethylamine (5.05g) in dichloromethane (140 ml) was cooled to 0° C. and methanesulphonylchloride (4.73 g) was added dropwise. The reaction mixture was stirredat ambient temperature for 2 hours and quenched with water (100 ml). Theorganic phase was washed with 2N aqueous hydrochloric acid solution (75ml) and 2N aqueous sodium hydroxide solution (75 ml), dried (MgSO₄) andthe solvent removed by evaporation. Thus was obtainedN-methyl-(4-tolyl)methanesulphonamide (5.3 g, 65%), m.p. 49°-52° C.

A solution of N-methyl-N-(4-tolyl)methanesulphonamide (0.31 g, 1.54mmol), N-bromosuccinimide (0.28 g, 1.55 mmol) and2,2'-azobisisobutyronitrile (20 mg) in carbon tetrachloride (20 ml) wasrefluxed for 2 hours. The mixture was then cooled to ambient temperatureand filtered. The solvent was evaporated and the residue partitionedbetween ethyl acetate (50 ml) and water (50 ml), washed with brine (50ml) and dried (MgSO₄). The solvent was evaporated yieldingN-(4-bromomethylphenyl)-N-methylmethanesulphonamide (0.24 g, 54%) whichwas used without further purification.

EXAMPLE 2

Using a similar procedure to that described in Example 1, except thatN-(4-bromomethyl-2-chlorophenyl)-N-methylmethanesulphonamide was used inplace of N-(4-bromomethylphenyl)-N-methylmethanesulphonamide, there wasobtainedN-{2-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenoxymethyl]phenyl}-N-methylmethanesulphonamide(0.34 g, 60%), m.p. 126°-128° C. (triturated with ether).

The N-(4-bromomethyl-2-chlorophenyl)-N-methylmethanesulphonamide used asstarting material was obtained as follows:

A solution of 2-chloro-4-methylaniline (5.00 g) and triethylamine (3.57g) in dichloromethane (100 ml) was cooled to 0° C. Methanesulphonylchloride (4.04 g) was added dropwise and the mixture stirred at ambienttemperature overnight. The mixture was then washed with 2N aqueoushydrochloric acid solution (50 ml) and the solvent removed byevaporation. The residue was dissolved in ethyl acetate (75 ml)extracted with 2N aqueous sodium hydroxide solution (2×50 ml). Theaqueous phase was acidified with 2N aqueous hydrochloric acid solutionand extracted with ethyl acetate (2×75 ml). This was subsequently dried(MgSO₄) and the solvent evaporated. Thus was obtainedN-(2-chloro-4-methylphenyl)methanesulphonamide (2.5 g, 32%).

NMR Spectrum 2.33 (3H, s), 2.97 (3H, s), 6.6 (1H, s), 7.10 (1H, d), 7.25(1H, s), 7.52 (1H, d).

A solution of the product so obtained (1.87 g) in DMF (20 ml) potassiumcarbonate (3.45 g) and methyl iodide (2.84 g) was stirred at ambienttemperature for 18 hours. The mixture was then quenched with water (100ml) and extracted with ethyl acetate (2×75 ml). The combined organicextracts were then washed with 2N aqueous sodium hydroxide solution (50ml), brine (50 ml) and dried (MgSO₄). The solvent was evaporated to giveN-(2-chloro-4-methylphenyl)-N-methylmethanesulphonamide as an oil (1.7g, 85%).

NMR Spectrum 2.35 (3H, s), 3.00 (3H, s), 3.28 (3H, s), 7.10 (1H, m),7.25 (1H, d), 7.36 (1H, d).

Bromination of N-(2-chloro-4-methylphenyl)-N-methylmethanesulphonamidewas carried out using a similar procedure to that described in Example1, except that N-(2-chloro-4-methylphenyl)-N-methylmethanesulphonamidewas used in place of N-methyl-N-(4-tolyl)-methanesulphonamide. There wasthus obtainedN-(4-bromomethyl-2-chlorophenyl)-N-methylmethanesulphonamide which wasused without further purification.

EXAMPLE 3

A solution of N-(4-iodophenyl)-N-methylmethanesulphonamide (0.31 g, 1mmol), 4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.22 g), potassiumcarbonate (20 mg) and copper (I) chloride (30 mg) in DMF (20 ml) washeated to 140° C. and stirred for 3 hours. Ethyl acetate (40 ml) andwater (40 ml) were added and the mixture was filtered through celite.The filtrate was washed with water (40 ml) and brine (40 ml), dried(MgSO₄) and the solvent evaporated. The product was purified by columnchromatography, thusN-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamidewas obtained as an oil (1.12 g, 42%).

NMR Spectrum 1.85-2.10 (4H, m), 2.85 (3H, s) 3.00 (3H, s), 3.30 (3H, s),3.75-3.90 (4H, m), 7.25-7.35 (8H, m).

The 4-(3-mercaptophenyl)-4-methoxytetrahydropyran used as startingmaterial was obtained as follows:

A solution of 1,3-dibromobenzene (23.8 g) in THF (120 ml) was cooled to-78° C. under an atmosphere of argon and n-butyl lithium (1.6M inhexane, 62.5 ml) was added dropwise. The mixture was stirred at -78° C.for 30 minutes and a solution of tetrahydropyran-4-one (10 g) in THF (40ml) was added. The resultant suspension was stirred at -78° C. for 1hour, allowed to warm to ambient temperature and then stirred for 30minutes. The mixture was poured into brine (250 ml) and extracted withdiethyl ether. The organic phase was dried (MgSO₄) and evaporated. Theresidue was triturated under hexane and the resultant solid (16.8 g) wasfiltered off.

A solution of the product so obtained in DMF (100 ml) was added dropwiseto a slurry of sodium hydride (60% w/w dispersion in mineral oil; 5.25g) in DMF (10 ml) and the mixture was stirred at ambient temperature for90 minutes. Methyl iodide (36.5 g) was added and the mixture was stirredat ambient temperature for 16 hours. Ethanol (2 ml) and water (500 ml)were added in turn and the mixture was extracted with diethyl ether(3×200 ml). The combined extracts were washed with water, dried (MgSO₄)and evaporated. The residue was purified by column chromatography usingincreasingly polar mixtures of hexane and ethyl acetate as eluent. Therewas thus obtained 4-(3-bromophenyl)-4-methoxytetrahydropyran (12 g, 44%)as a solid.

NMR Spectrum (CDCl₃, δ values) 1.88-2.1 (m, 4H), 3.0 (s, 3H), 3.78-3.95(m, 4H), 7.2-7.35 (m, 2H), 7.42 (m, 1H), 7.55 (m, 1H).

A solution of a portion (1 g) of the product so obtained in THF (4 ml)was cooled to -80° C. under an atmosphere of argon and n-butyl lithium(1.6M in hexane, 2.4 ml) was added dropwise. The mixture was stirred at-80° C. for 30 minutes, sulphur (0.12 g) was added and the mixture wasstirred at -80° C. for a further 30 minutes. Water (10 ml) was added andthe mixture was allowed to warm to ambient temperature. The mixture wasextracted with diethyl ether (10 ml). The aqueous phase was acidified topH4 by the addition of dilute aqueous hydrochloric acid solution andextracted with diethyl ether (2×10 ml). The combined organic extractswere dried (MgSO₄) and evaporated. There was thus obtained the requiredstarting material as an oil (0.5 g) which crystallised on standing andwas used without further purification.

The N-(4-iodophenyl)-N-methylmethanesulphonamide used as startingmaterial was obtained as follows:

A solution of 4-iodoaniline (3.50 g, 16 mmol) and pyridine (12.64 g) indichloromethane (120 ml) was stirred at ambient temperature.Methanesulphonyl chloride (1.83 g, 16 mmol) was added dropwise and thewhole mixture was stirred for 18 hours. The solvent was evaporated andthe residue partitioned between ethyl acetate (120 ml) and water (120ml). The organic phase was washed with 2N aqueous sulphuric acidsolution (2×75 ml), dried (MgSO₄) and the solvent evaporated. Thus wasobtained N-(4-iodophenyl)methanesulphonamide (2.04 g, 43%), m.p.131°-133° C. (recrystallised from ethyl acetate/hexane).

A solution of the product so obtained (0.89 g, 3 mmol) in acetone (50ml) with potassium carbonate (1.38 g) and methyl iodide (0.71 g, 5 mmol)was stirred at ambient temperature for 20 hours. Ethyl acetate (100 ml)was added to the mixture which was then washed with brine (50 ml), dried(MgSO₄) and the solvent evaporated. Thus was obtainedN-(4-iodophenyl)-N-methylmethanesulphonamide (0.56 g, 60%), m.p.103°-104° C. (recrystallised from ethyl acetate/hexane).

EXAMPLE 4

Using a similar procedure to that described in Example 3, except thatthe appropriate N-(4-iodophenyl)sulphonamide was used in place ofN-(4-iodophenyl)-N-methylmethanesulphonamide, there were obtained thecompounds described in the following table:

                  TABLE 1                                                         ______________________________________                                         ##STR2##                                                                     Ex 4                                                                          Compd.                              Yield                                     No.     .sub.-- N-Phenyl substituent                                                                R.sup.1 R.sup.2                                                                             (%)   m.p.                                ______________________________________                                        1.sup.a                                                                              3-chloro       methyl  methyl                                                                              76    oil                                 2.sup.b                                                                              no substituent methyl  H     68    oil                                 3.sup.c                                                                              no substituent methyl  ethyl 82    gum                                 4.sup.d                                                                              no substituent ethyl   methyl                                                                              82    gum                                 5.sup.e                                                                              3-methyl       methyl  methyl                                                                              35    gum                                 6.sup.f                                                                              2-chloro       methyl  methyl                                                                              48    gum                                 7.sup.g                                                                              no substituent methyl  allyl 31    gum                                 8.sup.h                                                                              no substituent methyl  benzyl                                                                              35    gum                                 9.sup.i                                                                              no substituent phenyl  methyl                                                                              30    gum                                 ______________________________________                                    

Notes

a. The product gave the following characteristic NMR signals: 1.90-2.10(4H, m), 2.85 (3H, s), 3.0 (3H, s), 3.30 (3H, s), 3.75-3.90 (4H, m),6.90 (1H, d), 7.15 (1H, m), 7.35-7.45 (4H, m), 7.50 (1H, d).

The N-(3-chloro-4-iodophenyl)-N-methylmethanesulphonamide used as astarting material was obtained using the procedures described in Example3 for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamideexcept that 3-chloro-4-iodoaniline was used to place of 4-iodoaniline.

b. The product gave the following characteristic NMR signals: 1.85-2.05(4H, m), 2.95 (3H, s), 3.05 (3H, s), 3.75-3,90 (4H, m), 6.65 (1H, s),7.15-7.40 (8H, m).

The N-(4-iodophenyl)methanesulphonamide used as starting material wasobtained as described in Example 3.

c. The product gave the following characteristic NMR signals: 1.15 (3H,t), 1.85-2.0 (4H, m), 2.85 (3H, s), 3.0 (3H, s), 3.70 (2H, q), 3.70-3.90(4H, m), 7.30-7.45 (8H, m).

The N-(4-iodophenyl)-N-ethylmethanesulphonamide used as startingmaterial was obtained as described in Example 3 for the preparation ofN-(4-iodophenyl)-N-methylmethanesulphonamide except that ethyl iodidewas used in place of methyl iodide.

d. The product gave the following characteristic NMR signals: 1.20 (3H,t), 1.80-1.95 (4H, m), 2.85 (3H, s), 3.15 (2H, q), 3.25 (3H, s),3.55-3.75 (4H, m), 7.25-7.45 (8H, m).

The N-(4-iodophenyl)-N-methylethanesulphonamide used as startingmaterial was obtained as follows:

To a solution of N-methylaniline (14.9 g) and triethylamine (15.1 g) indichloromethane (250 ml) at 0° C. was added acetyl chloride (11.0 g)dropwise. The mixture was stirred at ambient temperature for 1 hour,then washed with 2N aqueous hydrochloric acid solution (75 ml), dried(MgSO₄) and the solvent evaporated. Thus was obtainedN-methylacetanilide (15.6 g, 75%), m.p. 95°-97° C. (recrystallised fromethyl acetate/hexane).

The product so obtained (5.96 g), iodine (5.08 g) and iodic acid (2.29g) were heated in glacial acetic acid (30 ml) and concentrated sulphuricacid (4 ml) at 85° C. for 3.5 hours. The mixture was then cooled toambient temperature and ethyl acetate (125 ml) and water (75 ml) wereadded. Solid sodium bicarbonate was added to neutralise the mixturewhich was then washed with water (75 ml) and brine (75 ml). After drying(MgSO₄) the solvent was evaporated to leave 4'-iodo-N-methylacetanilide(7.04, 64%), m.p. 140°-141° C. (recrystallised from ethylacetate/hexane).

A solution of the product so obtained (6.05 g) in 2N aqueous sodiumhydroxide solution (30 ml) and ethanol (30 ml) was refluxed for 8 hours.The solvent was evaporated and the residue partitioned between ethylacetate (110 ml) and water (100 ml). The organic phase was washed withbrine (75 ml), dried (MgSO₄) and the solvent evaporated to give4-iodo-N-methylaniline as an oil (4.97 g, 97%).

NMR Spectrum 2.80 (3H, s), 6.40 (2H, d), 7.45 (2H, d).

The product so obtained was used in place of 4-iodoaniline in theprocedure described in Example 3 for the preparation ofN-(4-iodophenyl)methanesulphonamide and ethanesulphonyl chloride wasused in place of methanesulphonyl chloride. Thus was obtainedN-(4-iodophenyl)-N-methylethanesulphonamide as an oil.

NMR Spectrum 1.45 (3H, t), 3.00 (2H, q), 3.35 (3H, s), 7.15 (2H, m),7.70 (2H, m).

e. The product gave the following characteristic NMR signals: 1.85-2.05(4H, m), 2.38 (3H, s), 2.85 (3H, s), 2.96 (3H, s), 3.30 (3H, s),3.75-3.90 (4H, m), 7.05-7.35 (7H, m).

The N-(4-iodo-3-methylphenyl)-N-methylmethanesulphonamide used asstarting material was obtained as follows:

N-Methyl-N-(3-tolyl)methanesulphonamide was prepared as for thepreparation of N-(4-iodophenyl)-N-methylmethanesulphonamide described inExample 3, except that 3-methylaniline was used in place of4-iodoaniline.

A solution of N-methyl-N-(3-tolyl)methanesulphonamide (0.12 g), iodine(76 g) and iodic acid (35 mg) in glacial acetic acid (5 ml) andconcentrated sulphuric acid (0.6 ml) was stirred at 80° C. for 2.5hours. Ethyl acetate (40 ml) and water (40 ml) were then added and themixture neutralised with solid sodium bicarbonate. The organic phase waswashed with brine (30 ml), dried (MgSO₄) and the solvent evaporated toleave N-(4-iodo-3-methylphenyl)-N-methylmethanesulphonamide (0.22 g,90%), m.p. 85°-87° C.

f. The product gave the following characteristic NMR signals: 1.90-2.10(4H, m), 2.98 (3H, s), 3.02 (3H, s), 3.28 (3H, s), 3.75-3.90 (4H, m),7.05-7.55 (7H, m).

The N-(2-chloro-4-iodophenyl)-N-methylmethanesulphonamide used as astarting material was obtained using the procedure described in Example3 for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamideexcept that 2-chloro-4-iodoaniline was used in place of 4-iodoaniline.

g. The product gave the following characteristic NMR signals: 1.90-2.10(4H, m), 2.90 (3H, s), 3.0 (3H, s), 3.70-3.90 (4H, m), 4.24 (2H, d),5.15 (1H, d), 5.25 (1H, d), 5.70-5.95 (1H, m), 7.1-7.6 (8H, m).

The N-allyl-N-(4-iodophenyl)methanesulphonamide used as a startingmaterial was obtained using the procedures described in Example 3 forthe preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide, exceptthat allyl bromide was used in place of methyl iodide.

h. The product gave the following characteristic NMR signals: 1.85-2.05(4H, m), 2.95 (6H, s), 3.75-3.90 (4H, m), 4.82 (2H, s), 7.10-7.45 (13H,m).

The N-benzyl-N-(4-iodophenyl)methanesulphonamide used as a startingmaterial was obtained using the procedures described in Example 3 forthe preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide, exceptthat benzyl bromide was used in place of methyl iodide.

i. The product gave the following characteristic NMR signals: 1.85-2.05(4H, m), 2.97 (3H, s), 3.18 (3H, s), 375-3.90 (4H, m), 7.0-7.60 (13H,m).

The N-(4-iodophenyl)-N-methylbenzenesulphonamide used as a startingmaterial was obtained using the procedures described in Example 3 forthe preparation of N-(4-iodophenyl-N-methylmethanesulphonamide, exceptthat benzenesulphonyl chloride was used in place of methanesulphonylchloride.

EXAMPLE 5

A solution of 5-iodo-N-mesylindoline (0.32 g, 1 mmol),4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.23 g, 1 mmol), copper(I) chloride (30 mg) and potassium carbonate (0.28 g) in DMF (10 ml) washeated at 140° C. for 5 hours. After cooling ethyl acetate (75 ml) andwater (75 ml) were added and the mixture was filtered through celite.The filtrate was washed with brine (50 ml), dried (MgSO₄) and thesolvent evaporated. The crude product was purified by columnchromatography to give5-[3-(4-methoxytetrahydropyran-4yl)phenylthio]-N-mesylindoline (0.23 g,55%), m.p. 114°-118° C. (recrystallised from ethyl acetate/hexane).

NMR Spectrum 1.80-2.08 (4H, m), 2.90 (3H, s), 2.95 (3H, s), 3.12 (2H,t), 3.72-3.90 (4H, m), 4.00 (2H, t), 7.10-7.40 (7H, m).

The 5-iodo-N-mesylindoline used as starting material was prepared asfollows:

N-mesylindoline was obtained using the procedure described in Example 3for the preparation of N-(4-iodophenyl)methanesulphonamide, except thatindoline was used in place of 4-iodoaniline. The N-mesylindoline soobtained (0.67 g, 5 mmol), iodine (0.65 g) and iodic acid (0.29 g) inglacial acetic acid (4 ml) and concentrated sulphuric acid (0.5 ml) wereheated to 85° C. for 2 hours. The mixture was diluted with water (75 ml)and ethyl acetate (75 ml) and neutralised with solid sodium bicarbonate.The organic phase was washed with brine (50 ml), dried (MgSO₄) treatedwith charcoal (1 g), filtered and the solvent evaporated. Polar materialwas removed by filtration through silica and the 5-iodo-N-mesylindolinethus obtained was used without further purification.

EXAMPLE 6

Using a similar procedure to that described in Example 5, except thatthe appropriate iodosulphonamide was used in place of5-iodo-N-mesylindoline, there were obtained the compounds described inthe following table:

                  TABLE II                                                        ______________________________________                                         ##STR3##                                                                     Ex 6                                                                          Compd.                                                                        No.        X"             R'      m.p.                                        ______________________________________                                        1.sup.a    CH.sub.2 CH.sub.2 CH.sub.2                                                                   methyl  gum                                         2.sup.b    CH.sub.2 CH.sub.2                                                                            ethyl   gum                                         ______________________________________                                    

Notes

a. The product gave the following characteristic NMR signals: 1.85-2.10(6H, m), 2.80 (2H, t), 2.92 (3H, s), 2.98 (3H, s), 3.75-3.90 (6H, m),7.10-7.65 (7H, m).

The 6-iodo-N-mesyl-1,2,3,4-tetrahydroquinoline used as starting materialwas obtained using the procedures described in Example 5 for thepreparation of 5-iodo-N-mesylindoline except that1,2,3,4-tetrahydroquinoline was used in place of indoline.

b. The product gave the following characteristic NMR signals: 1.38 (3H,t), 1.82-2.05 (4H, m), 2.96 (3H, s), 3.05-3.20 (4H, m), 3.75-3.90 (4H,m), 4.10 (2H, m), 7.10-7.35 (7H, m).

The 5-iodo-N-ethylsulphonylindoline used as starting material wasobtained using the procedures described in Example 5 for the preparationof 5-iodo-N-mesylindoline, except that ethanesulphonyl chloride was usedin place of methanesulphonyl chloride.

EXAMPLE 7

Sodium hydride (79 mg, 50% dispersion in mineral oil, 1.65 mmol) wasadded to a solution ofN-(6-chloropyrid-3-yl)-N-methylmethanesulphonamide (0.33 g) and4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.34 g) in DMF (10 ml).The mixture was stirred at ambient temperature for 15 minutes and heatedat 140° C. for 1.5 hours. After cooling, it was partitioned betweenwater (75 ml) and ethyl acetate (75 ml). The organic phase was washedwith brine (50 ml), dried (MgSO₄) and the solvent evaporated. Theproduct was purified by column chromatography to giveN-{6-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]pyrid-3-yl}-N-methylmethanesulphonamideas a gum (0.25) g, 41%).

NMR Spectrum 1.85-2.10 (4H, m), 2.85 (3H, s), 3.0 (3H, s), 3.30 (3H, s),3.75-3.90 (3H, s), 6.90 (1H, d), 7.45-7.65 (5H, m), 8.40 (1H, d).

The N-(6-Chloropyrid-3-yl)-N-methylmethanesulphonamide used as startingmaterial was prepared as follows:

N-(2-chloropyrid-5-yl)methanesulphonamide was obtained using theprocedure described for the preparation ofN-(4-iodophenyl)methanesulphonamide, except that5-amino-2-chloropyridine was used in place of 4-iodoaniline.

Sodium hydride (0.12 g, 50% dispersion in mineral oil, 2.5 mmol) wasadded to a solution of the product so obtained (0.50 g) in DMF (10 ml).The mixture was stirred at ambient temperature for 15 minutes. Methyliodide (0.36 g) was added and the mixture stirred at ambient temperaturefor a further 1 hours. The mixture was partitioned between water (75 ml)and ethyl acetate (75 ml), the organic phase washed with water (50 ml)and brine (50 ml), dried (MgSO₄) and the solvent evaporated to leaveN-(6-chloropyrid-3-yl)-N-methylmethanesulphonamide (0.40 g, 75%), m.p.87°-90° C.

EXAMPLE 8

Using a similar procedure to that described in Example 3, except thatthe appropriate N-(4-iodophenyl)sulphonamide was used in place ofN-(4-iodophenyl)-N-methylmethanesulphonamide, there were obtained thecompounds described in the following table:

                  TABLE III                                                       ______________________________________                                         ##STR4##                                                                     Ex. 8                                                                         Compd.   .sub.-- N-Phenyl       Yield m.p.                                    No.     Substituent                                                                              R.sup.1 R.sup.2                                                                            (%)   (°C.)                            ______________________________________                                        1.sup.a 2-chloro   methyl  H    50    101-102                                 2.sup.b no substituent                                                                           phenyl  H    37    gum                                     ______________________________________                                    

Notes

a. The product was recrystallised from a mixture of hexane and ethylacetate. N-(4-Iodophenyl)methanesulphonamide is described in the portionof Example 3 which is concerned with the preparation of startingmaterials.

b. The product gave the following characteristic NMR signals: 1.85-2.05(4H, m), 2.93 (3H, s), 3.75-3.90 (4H, m), 6.95-7.8 (13H, m).

The N-(4-iodophenyl)benzenesulphonamide used as a starting material wasobtained by the reaction of benzenesulphonyl chloride and 4-iodoanilineusing a similar procedure to that described in the portion of Example 3which is concerned with the preparation ofN-(4-iodophenyl)methanesulphonamide.

EXAMPLE 9

Using a similar procedure to that described in Example 3, except thatthe appropriate N-(4-iodophenyl)sulphonamide was used in place ofN-(4-iodophenyl)-N-methylmethanesulphonamide and that4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran was used in placeof 4-(3-mercaptophenyl)-4-methoxytetrahydropyran, there were obtainedthe compounds described in the following table:

                  TABLE IV                                                        ______________________________________                                         ##STR5##                                                                     Ex. 9                                                                         Compd.  .sub.-- N-Phenyl         Yield m.p.                                   No.    Substituent R.sup.1 R.sup.2                                                                             (%)   (°C.)                           ______________________________________                                        1.sup.a                                                                              no substituent                                                                            methyl  methyl                                                                              67    108-111                                2.sup.a                                                                              3-chloro    methyl  methyl                                                                              60    113-115                                3.sup.b                                                                              2-chloro    methyl  H     73    gum                                    4.sup.c                                                                              3-chloro    methyl  H     44    gum                                    5.sup.d                                                                              2-fluoro    methyl  H     58    101-102                                ______________________________________                                    

Notes

The 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran used as astarting material for each of the compounds described in Table IV wasobtained as follows:

Benzyl mercaptan (0.94 ml) was added drop wise to a mixture of sodiumhydride (60% w/w dispersion in mineral oil; 0.35 g) and DMF (5 ml) whichwas cooled in a water bath. The mixture was stirred at ambienttemperature for 30 minutes. The mixture so obtained was added dropwiseto a mixture of 1-bromo-3,5-difluorobenzene (2.78 ml) and DMF (5 ml)which was cooled in an ice bath to 5° C. The resultant mixture wasstirred at ambient temperature for 1 hour. The mixture was partitionedbetween diethyl ether and water. The organic phase was washed withwater, dried (MgSO₄) and evaporated. There was thus obtained benzyl3-bromo-5-fluorophenyl sulphide (2.5 g).

NMR Spectrum (CDCl₃, δ values) 4.13 (s, 2H), 6.90 (m, 1H), 7.04 (m, 1H),7.2-7.35 (m, 6H).

A Grignard reagent was prepared by heating a mixture of1,2-dibromoethane (10 drops), magnesium (0.24 g) and THF (25 ml) to 60°C. for 5 minutes, by adding benzyl 3-bromo-5-fluorophenyl sulphide (2.5g) and by heating the resultant mixture to 60° C. for 30 minutes. Thereagent was cooled in an ice bath, tetrahydropyran-4-one (0.8 ml) wasadded and the mixture was stirred for 30 minutes and then allowed towarm to ambient temperature. A saturated aqueous ammonium chloridesolution (30 ml) was added and the mixture was partitioned betweendiethyl ether and water. The organic phase was washed with water andwith brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using initially hexane and then increasingly polarmixtures of hexane and ethyl acetate as eluent. There was thus obtained4-(3-benzylthio-5-fluorophenyl)-4-hydroxytetrahydropyran (1.02 g).

Sodium hydride (60% w/w dispersion in mineral oil; 0.2 g) was addedportionwise to a mixture of the product so obtained and DMF (5 ml) andthe mixture was stirred at ambient temperature for 1 hour. Methyl iodide(0.6 ml) was added and the mixture was stirred at ambient temperaturefor 1 hour. The mixture was partitioned between diethyl ether and water.The organic phase was dried (MgSO₄) and evaporated. There was thusobtained 4-(3-benzylthio-5-fluorophenyl)-4-methoxytetrahydropyran (0.8g) as an oil.

NMR Spectrum (CDCl₃, δ values(1.85 (m, 4H), 2.91 (s, 3H), 3.78 (m, 4H),4.12 (s, 2H), 6.85-7.05 (m, 3H), 7.25 (m, 5H).

3 -Chloroperbenzoic acid (55% w/w technical grade; 0.38 g) was addedportionwise to a mixture of a portion (0.4 g) of the product so obtainedand chloroform (4 ml) which was cooled in an ice bath to 0° C. Themixture was stirred at 0° C. for 30 minutes and then allowed to warm toambient temperature. Calcium hydroxide (0.13 g) was added and themixture was stirred at ambient temperature for 15 minutes. The mixturewas filtered and the filtrate was evaporated. Trifluoroacetic anhydride(3 ml) was added to the residue so obtained and the mixture was heatedto reflux for 30 minutes. The mixture was evaporated. Methanol (10 ml)and triethylamine (10 ml) were added to the residue and the resultantmixture was evaporated. There was thus obtained4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran (0.37 g) as a gumwhich was used as the required starting material without furtherpurification.

a. The product was recrystallised from a mixture of hexane and ethylacetate.

b. The product gave the following characteristic NMR signals: 1.85-2.05(4H, m), 3.0 (3H, s), 3.05 (3H, s), 3.75 (4H, m), 6.85-7.22 (4H, m),7.43 (1H, d), 7.63 (1H, d).

The N-(2-chloro-4-iodophenyl)methanesulphonamide used as a startingmaterial was obtained by the reaction of 2-chloro-4-iodoaniline andmethanesulphonyl chloride using a similar procedure to that described inthe portion of Example 3 which is concerned with the preparation ofN-(4-iodophenyl)methanesulphonamide.

c. The product gave the following characteristic NMR signals: 1.85-2.05(4H, m), 2.98 (3H, s), 3.08 (3H, s), 3.75-3.9 (4H, m), 6.85-7.38 (6H,m).

The N-(3-chloro-4-iodophenyl)methanesulphonamide used as a startingmaterial was obtained by the reaction of 3-chloro-4-iodoaniline andmethanesulphonyl chloride using a similar procedure to that described inthe portion of Example 3 which is concerned with the preparation ofN-(4-iodophenyl)methansulphonamide.

d. The product was recrystallised from a mixture of hexane and ethylacetate.

the N-(2-fluoro-4-iodophenyl)methanesulphonamide, m.p. 117°-119° C.,used as a starting material was obtained in 70% yield by the reactionsof 2-fluoro-4-iodoaniline and methanesulphonyl chloride using a similarprocedure to that described in the portion of Example 3 which isconcerned with the preparation of N-(4-iodophenyl)-methanesulphonamide.

EXAMPLE 10

Using a similar procedure to that described in Example 3, except thatthe appropriate N-(4-iodophenyl)sulphonamide was used in place ofN-(4-iodophenyl)-N-methylmethanesulphonamide and that4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran was used in placeof 4-(3-mercaptophenyl)-4-methoxytetrahydropyran, there were obtainedthe compounds described in the following table:

                  TABLE V                                                         ______________________________________                                         ##STR6##                                                                     Ex. 10                                                                        Compd.                           Yield                                                                              m.p.                                    No.     R.sup.1          R.sup.2 (%)  (°C.)                            ______________________________________                                        1.sup.a ethyl            H       45   78-81                                   2.sup.b phenyl           H       45   gum                                     3.sup.c 2-methoxycarbonylphenyl                                                                        H       44   92-94                                   4.sup.d 1-naphthyl       H       68   138-139                                 5.sup.e 8-quinolyl       H       15   gum                                     6.sup.f 8-quinolyl       methyl  35   gum                                     ______________________________________                                    

Notes

a. The produce was recrystallised from a mixture of hexane and ethylacetate.

The N-(2-fluoro-4-iodophenyl)ethanesulphonamide used as a startingmaterial was obtained by the reaction of 2-fluoro-4-iodoaniline andethanesulphonyl chloride using a similar procedure to that described inthe portion of Example 3 which is concerned with the preparation ofN-(4-iodophenyl)methanesulphonamide. There was thus obtained therequired starting material in 77% yield, m.p. 66°-68° C.

b. The product gave the following characteristic NMR signals: 1.82-2.05(m, 4H), 2.96 (s, 3H), 3.76-3.88 (m, 4H), 6.8 (m, 2H), 6.97 (m, 2H),7.12 (m, 2H), 7.41-7.62 (m, 4H), 7.8 (m, 2H).

The N-(2-fluoro-4-iodophenyl)benzenesulphonamide used as a startingmaterial was obtained by the reaction of 2-fluoro-4-iodoaniline andbenzenesulphonyl chloride using a conventional procedure as described inExample 3. There was thus obtained the required starting material in 50%yield, m.p. 150°-152° C.

c. The produce was recrystallised from a mixture of hexane and ethylacetate.

The N-(2-fluoro-4-iodophenyl)-2-methoxycarbonylbenzene-sulphonamide usedas a starting material was obtained by the reaction of2-fluoro-4-iodoaniline and 2-methoxycarbonylbenzenesulphonyl chlorideusing a conventional procedure as described in Example 3. There was thusobtained the required starting material in 58% yield, m.p. 103°-104° C.

d. The produce was recrystallised from a mixture of hexane and ethylacetate.

The N-(2-fluoro-4-iodophenyl)-1-naphthalene sulphonamide used as astarting material was obtained by the reaction of 2-fluoro-4-iodoanilineand 1-naphthalenesulphonyl chloride using a conventional procedure asdescribed in Example 3. There was thus obtained the required startingmaterial in 44% yield, m.p. 130°-132° C.

e. The product gave the following characteristic NMR signals: 1.74-2.02(m, 4H), 2.92 (s, 3H), 3.70-3.90 (m, 4H), 6.70 (m, 1H), 6.82 (m, 1H),6.92 (m, 1H), 7.04 (m, 2H), 7.52-7.73 (m, 3H), 8.06 (m, 1H), 8.30 (m,1H, 8.38 (m, 1H), 9.11 (m, 1H).

The N-(2-fluoro-4-iodophenyl)-8-quinolinesulphonamide used as a startingmaterial was obtained by the reaction of 2-fluoro-4-iodoaniline and8-quinolinesulphonyl chloride using a conventional procedure asdescribed in Example 3. There was thus obtained the required startingmaterial in 39% yield, m.p. 154°-156° C.

f. The product gave the following characteristics NMR signals: 1.83-2.02(m, 4H), 2.97 (s, 3H), 3.54 (s, 3H), 3.73-3.90 (m, 4H), 6.83 (m, 1H),6.91-7.08 (m, 3H), 7.18 (m, 1H), 7.30 (m, 1H), 7.51 (m, 2H), 8.03 (m,1H), 8.23 (m, 1H), 8.37 (m, 1H), 8.98 (m, 1H).

The N-(2-fluoro-4-iodophenyl)-N-methyl-8-quinolinesulphonamide used as astarting material was obtained by the reaction ofN-(2-fluoro-4-iodophenyl)-8-quinolinesulphonamide and methyl iodideusing a conventional procedure as described in the last paragraph ofExample 3. There was thus obtained the required starting material in 55%yield, m.p. 90°-93° C. ##STR7##

I claim:
 1. A sulphonamide derivative of the formula Iwherein R¹ is(1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and wherein R² and R³together form a group of the formula --A² --X² --A³ -- which, togetherwith the carbon atom to which A² and A³ are attached, defines a ringhaving 6 ring atoms, wherein A² and A³, which may be the same ordifferent, each is (1-3C)alkylene and X² is oxy, and which ring may bearone, two or three substituents, which may be the same or different,selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy; wherein A¹ is adirect link to X¹ or is (1-3C)alkylene; wherein X¹ is oxy, thio,sulphinyl, sulphonyl or imino; wherein Ar is phenylene which mayoptionally bear one or two substituents selected from halogeno, hydroxy,amino, nitro, cyano, carbamoyl, ureido, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl and (2-4C)alkanoylamino; andwherein Q is of the formula CR⁷, wherein R⁷ is hydrogen, halogeno,(1-4C), (1-4C)alkoxy, hydroxy, amino, nitro, cyano, carbamoyl, ureido,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl,(2-4C)alkanoylamino or (2-4C)alkenyl; wherein R⁴ is (1-4C)alkyl,(3-4C)alkenyl or (3-4C)alkynyl or R⁴ is phenyl, benzyl or pyridyl eachof which may optionally bear one or two substituents selected fromhalogeno, (1-4C)alkoxy, (1-4C)alkyl, hydroxy, cyano, nitro, amino,trifluoromethyl, carbamoyl, ureido, (1-4C)alkylamino,di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino; wherein R⁵ is hydrogen,(1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl, or R⁵ is phenyl, benzyl, orpyridyl each of which may optionally bear one or two substituentsselected from halogeno, (1-4C)alkoxy, (1-4C)alkyl, hydroxy, cyano,nitro, amino, trifluoromethyl, carbamoyl, ureido, (1-4C)alkylamino,di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino; wherein R⁶ is hydrogen,halogeno, (1-4C)alkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano,carbamoyl, ureido (1-4C)alkylamino, di-[(1-4C)-alkyl]amino,fluoro-(1-4C)alkyl or (2-4C)alkanoylamino;or a pharmaceuticallyacceptable salt thereof.
 2. A sulphonamide derivative of the formula Ias claimed in claim 1 wherein R⁴ may be phenyl, benzyl, naphthyl, orpyridyl each of which may optionally bear one or two substituentsselected from halogeno, (1-4C)alkoxy, (1-4C)alkyl, hydroxy, cyano,nitro, amino, trifluoromethyl, carbamoyl, ureido, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino and (1-4C)alkoxycarbonyl; ora pharmaceutically-acceptable salt thereof.
 3. A sulphonamide derivativeof the formula I as claimed in claim 1 wherein R¹ is methyl;R² and R³together form a group of the formula --A² --X² --A³ -- which, togetherwith the carbon atom to which A² and A³ are attached, defines a ringhaving 6 ring atoms, wherein each of A² and A³ is ethylene and X² ixoxy, and which ring may bear a methyl or ethyl substituent alpha to X² ;A¹ is a direct link to X¹, or is methylene; X¹ is thio or oxy; Ar is1,3-phenylene which may optionally bear a fluoro substituent; Q is ofthe formula CR⁷ wherein R⁷ is hydrogen, methyl or chloro; R⁴ is methyl,ethyl or phenyl; R⁵ is hydrogen, methyl, ethyl, allyl or benzyl; and R⁶is hydrogen, methyl or chloro; oror a pharmaceutically-acceptable saltthereof.
 4. A sulphonamide derivative of the formula I as claimed inclaim 1 whereinR¹ is methyl; R² and R³ together form a group of theformula --A² --X² --A³ -- which, together with the carbon atom to whichA² and A³ are attached, defines a ring having 6 ring atoms, wherein eachof A² and A³ is ethylene and X² is oxy, and which ring may bear a methylor ethyl substituent alpha to X² ; A¹ is a direct link to X¹, or ismethylene; X¹ is thio or oxy; Ar is 1,3-phenylene which may optionallybear a fluoro substituent; Q is of the formula CR⁷ wherein R⁷ ishydrogen, methyl or chloro; R⁴ is methyl, ethyl or phenyl; R⁵ ishydrogen; R⁶ is hydrogen, methyl, fluoro or chloro;or apharmaceutically-acceptable salt thereof.
 5. A sulphonamide derivativeof the formula I as claimed in claim 1 whereinR¹ is methyl; R² and R³together form a group of the formula --A² --X² --A³ -- which, togetherwith the carbon atom to which A² and A³ are attached, defines a ringhaving 6 ring atoms, wherein each of A² and A³ is ethylene and X² isoxy, and which ring may bear a methyl or ethyl substituent alpha to X² ;A¹ is a direct link to X¹ ; X¹ is thio; Ar is 1,3-phenylene which mayoptionally bear a fluoro substituent; Q is of the formula CR⁷ wherein R⁷is hydrogen or chloro; R⁴ is methyl, ethyl, phenyl, or2-methoxycarbonylphenyl; R⁵ is hydrogen; R⁶ is hydrogen, fluoro orchloro;or a pharmaceutically-acceptable salt thereof.
 6. A sulphonamidederivative of the formula I, or a pharmaceutically-acceptable saltthereof, as claimed in claim 1 selectedfromN-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamide,N-{3-chloro-4-[3-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamide,N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-ethylmethanesulphonamideandN-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylethanesulphonamide.7. A sulphonamide derivative of the formula I, or apharmaceutically-acceptable salt thereof, as claimed in claim 1 selectedfromN-{2-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-methanesulphonamide,N-{2-chloro-4-[4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)-phenylthio]phenyl}methanesulphonamide,N-{3-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)-phenylthio]phenyl}methanesulphonamideandN-{2-fluoro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)-phenylthio]phenyl}methanesulphonamide.8. A pharmaceutical composition which comprises a sulphonamidederivative of the formula I, or a pharmaceutically-acceptable saltthereof, as claimed in any one or claims 1 to 7 in association with apharmaceutically-acceptable diluent or carrier.
 9. A method of treatinga disease or medical condition mediated alone or in part by one or moreleukotrienes which comprises administering to a warm-blooded animalrequiring such treatment an effective amount of a sulphonamidederivative of the formula I, or a pharmaceutically-acceptable saltthereof, as claimed in any one of claims 1 to 7.